Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C[Mg+].[Br-].[C:13](OC(=O)C)(=[O:15])[CH3:14].[C:20](=O)(O)[O-].[Na+]>C1COCC1.CCOCC.C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:9][C:13](=[O:15])[CH3:14])=[CH2:20])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(F)cn1
Reactant: O=C([O-])O
Reactant: CC(=O)OC(C)=O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C(NC(C)=O)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
5-Fluoropyrimidine-2-carbonitrile (Method 59, 1.0 g, 8.1 mmol) in THF (10 ml) was added a solution of MeMgBr (3.3 ml, 9.75 mmol) in ether drop wise at 0° C. After addition, the reaction was warmed to room temperature, stirred at room temperature for 1 hour and then diluted with DCM (10 ml). Acetic anhydride (1.23 ml, 13.0 mmol) was added in one portion. The reaction was stirred at room temperature for 1 hour and 40° C. for 1 hour. Saturated sodium bicarbonate solution (10 ml) was added and extracted with EtOAc (2×20 ml). The combined organic was dried over sodium sulfate. After removal of solvent, the resulted residue was purified by column chromatography (hexane-EtOAc=2.5:1) to give the title compound as a white solid (0.38 g, 26%). 1H NMR (400 MHz) 9.34 (s, 1H), 8.95 (s, 2H), 6.25 (s, 1H), 6.03 (s, 1H), 2.11 (s, 3H). MS: Calcd.: 181. Found: [M+H]+ 182.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH:9]=2)=[C:4]([CH3:31])[CH:3]=1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:21])=[CH:18][CH:17]=3)[CH:9]=2)=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1cc(C(Oc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Reactant: CCOC(=O)CCNC
Product: Cc1cc(Cl)ccc1-c1cc(C(Oc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)o1
Yield: 100.3 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-{[5-(4-chloro-2-methylphenyl)-2-methyl-3-furyl](cyclohexyl)methoxy}benzoic acid (162 mg) as well as ethyl 3-(methylamino)propanoate (59 mg) to give the title compound (194 mg, 99%) as an amorphous compound.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26])=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1[C@H](N)C(=O)N1OCC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
(3S-trans) -[[3-[(t-Butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid. phenylmethyl ester (3.6g) was dissolved in 5 ml of dichloromethane and the solution was cooled to -10° C. Trifluoroacetic acid (25ml) was added dropwise and the mixture was stirred for 20 minutes at -10° C. After evaporation, the residue was treated with ether yielding 2.5 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH:16]=1)=[O:4].[H][H]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cnccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnccc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.6 %

Procedure:
A solution of Pd(OH)2/C (5.2 g, 7.4 mmol, 0.3 eq., 20%) in EtOAc (100 mL) was stirred for 10 minutes at room temperature under nitrogen. 3,6-Dihydro-2H-[4,4′]bipyridinyl-1,3′-dicarboxylic acid 1-t-butyl ester 3′-methyl ester (8.7 g, 27.3 mmol, 1.0 eq.) was added. Hydrogen gas was introduced into the reaction vessel (at 1 atm) and the solution was stirred for 5 hours at room temperature. The solids were filtered and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1:5) to yield 3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1,3′-dicarboxylic acid 1-t-butyl ester 3′-methyl ester (6.7 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[Cl:24]CCl>>[Cl:24][C:9]1[N:10]=[CH:2][C:3]([C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:5])=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)nc1)N1CCOCC1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of chloronicotinoyl chloride (3.52 g, 2.00 mmol) and triethylamine (3.1 mL, 2.22 mmol) in dichloromethane (5 mL) at 0° C. was slowly added morpholine (1.75 mL, 2.00 mmol). The mixture was warmed to ambient temperature, washed with water (2×25 mL), brine (1×25 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The product was chromatographed on silica with ethyl acetate to give the titled compound (4.0 g, 88%). MS (DCI) m/z 227 (M+H)+;
Reaction SMILES: CS[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[S:4].[NH2:11][CH2:12][C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].C(N(CC)CC)C>CO.C(OCC)(=O)C>[CH:16]1([NH:15][C:13](=[O:14])[CH2:12][NH:11][C:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)=[S:4])[CH2:18][CH2:17]1
Reactant: NCC(=O)NC1CC1
Reactant: CSC(=S)c1cccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CNC(=S)c1cccnc1)NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of methylpyridine-3-carbodithioate (2.97 g, 17.52 mmol) in methanol (10 mL) was added a solution of 2-amino-N-cyclopropylacetamide (2 g, 17.52 mmol) (HCl salt) and triethylamine (3.55 g, 35.0 mmol). The mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate and washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-cyclopropyl-2-(pyridine-3-carbothioamido)acetamide as a yellow solid (3.60 g, 83%): mp 152-153° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.91 (ddd, J=7.0, 2.3, 0.7 Hz, 1H), 8.76-8.56 (m, 1H), 8.10 (m, 2H), 7.57-7.32 (m, 1H), 4.26 (m, 2H), 2.73-2.57 (m, 1H), 0.77-0.61 (m, 2H), 0.50-0.29 (m, 2H); ESIMS (m/z) 234 ([M−H]−).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].[OH-].[Na+].Cl>C(Cl)(Cl)Cl.O>[C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)CCCCCCCCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
Compound I (50 g, 0.204 mol), prepared according to the general method described in Example 1, was dissolved in 2500 ml of chloroform, followed by the addition of a solution of 43.1 g (0.214 mol) of 11-aminoundecanoic acid and 60.0 g (1.5 mmol) of sodium hydroxide in 1500 ml of water. The mixture was stirred vigorously for one hour in a 5 liter Morton flask to insure thorough mixing of the two layers. The mixture was acidified with 250 ml of concentrated hydrochloric acid and stirred an additional 30 minutes. The organic layer was separated and the aqueous was extracted with 3×500 ml of chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give a solid. The product was recrystallized from toluene to give 68.37 g (82%) of 11-(4-benzoylbenzamido)undecanoic acid with a melting point of 107-109° C. Analysis on an NMR spectrometer was consistent with the desired product: 1H NMR (CDCl3) aromatic protons 7.20-7.80 (m, 9H), amide NH 6.30 (broad t, 1H), methylene adjacent to amide N 3.35 (in, 2H), methylene adjacent to carbonyl 2.25 (t, 2H), and remaining methylenes 1.00-1.80 (m, 16H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][C:9]=2[F:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)ccc(F)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2c(Cl)ccc(F)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=399.4 (M+H+) and αD20=−54.7, was prepared in accordance with the general method of example 12b) from 4-chloro-7-fluoro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[C:14]=3[Cl:22])[C:5]2=[N:4][C:3]=1[CH3:23].N1C=CC=CC=1.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>ClCCl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:31]([O:33][C:34]4[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=4)=[O:32])[C:14]=3[Cl:22])[C:5]2=[N:4][C:3]=1[CH3:23]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)Oc4ccc([N+](=O)[O-])cc4)c3Cl)cccn2c1Br
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 3-bromo-8-(2,6-dichloro-3-methylaminobenzyloxy)-2-methylimidazo[1,2-a]pyridine (68 mg) and pyridine (0.5 ml) in dichloromethane (2 ml) was added 4-nitrophenyl chloroformate (40 mg) at ambient temperature. After stirring for 1 hour, the mixture was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane twice. The organic layers were combined, washed with water twice and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-bromo-8-[2,6-dichloro-3-[N-methyl-N-(4-nitrophenoxycarbonyl) amino]benzyloxy]-2-methylimidazo-[1,2-a]pyridine (84 mg) as crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[OH:29])([CH3:22])[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:49][C@@H:50]2[CH2:54][O:53][C:52](=[O:55])[NH:51]2)(=O)=O)=CC=1>C(#N)C.O>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([CH3:22])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:49][C@H:50]4[CH2:54][O:53][C:52](=[O:55])[NH:51]4)[CH3:21])[C:14]3=[O:30])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(=O)N2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2O)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OC[C@H]2COC(=O)N2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 97.1 %

Procedure:
A solution of N-cyclopropyl-3-(3-(2-(2-hydroxyphenyl)propan-2-ylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzamide (Example 134, 0.5 g) in acetonitrile (10 mL) was treated with potassium carbonate (0.495 g) and (S)-(2-oxooxazolidin-4-yl)methyl 4-methylbenzenesulfonate (0.324 g) under nitrogen. The resulting mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water, and extracted with DCM. The organic layer was dried (MgSO4), filtered and evaporated to afford the subtitle compound as a solid (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([C:13]([O:15]C)=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([C:13]([OH:15])=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2ccc(Cl)cc2c1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc2ccc(Cl)cc2c1C(F)(F)F
Reaction time: 4 h

Procedure:
A mixture of compound 18e (574 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) in THF/MeOH/H2O (4/4/4 mL) was stirred for 4 h. A 15% citric acid solution (20 mL) was added, and the mixture was then extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue, compound 18f, was dried under reduced pressure for 18 h and was used without purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12](=[O:33])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][C:28]([CH:31]=[CH2:32])=[CH:29][CH:30]=4)[N:22]=[N:21]3)[CH:14]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][NH2:42]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12](=[O:33])[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][C:28]([CH2:31][CH2:32][NH:42][CH3:41])=[CH:29][CH:30]=4)[N:22]=[N:21]3)[CH:14]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1ccc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)cn1
Reactant: CN
Product: CNCCc1ccc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)cn1

Procedure:
Example 162 was prepared from N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(6-vinyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzamide (Example 151) and methylamine in the same manner as Example 151. ESI MS m/z 592 [C30H37N7O4S+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(#N)C>[F:29][C:17]([F:16])([F:28])[C:18]1[CH:19]=[C:20]([S:24]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(C#N)=NOS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1OC

Procedure:
As described under 1.2., 4.1 g (0.02 mol) of a-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted with 5.4 g (0.022 mol) of 3-trifluoromethylphenylsulfonic acid chloride in the presence of triethylamine. After recrystallisation of the crude product from ethyl acetate/-hexane, 6.6 g (80%) of α-(3-trifluoromethyl-phenylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of yellowish crystals having a melting point of 129-130° C. The 1H-NMR spectrum of the compound shows that it is a pure stereoisomer. The UV spectrum (acetonitrile) of the substance shows a broad absorption band with a maximum at 351 nm (ε=11700) that extends to 430 nm. Elemental analysis: C17H13F3N2O5S (414.36)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[O:15][CH:16]([CH3:18])[CH3:17].[H-].[Na+].[CH2:21]([O:23][CH2:24]Cl)[CH3:22]>CN(C)C=O.CCCCCC>[CH2:21]([O:23][CH2:24][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([O:15][CH:16]([CH3:18])[CH3:17])=[C:7]1[C:12]([NH2:14])=[O:13])[CH3:22]
Reactant: COc1ccc2[nH]c(C(N)=O)c(OC(C)C)c2c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOCn1c(C(N)=O)c(OC(C)C)c2cc(OC)ccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.3 %

Procedure:
5-Methoxy-3-(1-methylethoxy)-1H-indole-2-carboxamide (328 mg, 1.32 mmol) in 5 mL of dimethylformamide is added to a suspension of sodium hydride (60% by weight) (67 mg, 1.67 mol) in 5 mL of dimethylformamide. After 1.5 hours the mixture is cooled to 0° C. and chloromethyl ethyl ether (160 μL, 1.72 mmol) is added dropwise, and the solution is stirred at 0° C. for 20 minutes and then at room temperature for 1.5 hours. The reaction mixture is diluted with 1:1 hexane:ethyl acetate and washed with brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. Chromatography eluting with 1:1 ethyl acetate:hexane gives 240 mg (51%) of 1-ethoxymethyl-5-methoxy-3-(1-methylethoxy)-1H-indole-2-carboxamide; mp 110°-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:20]=[O:21].C(OCC)(=O)C>C1COCC1.C(=O)=O.CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[C:4]([CH:3]=1)[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1F
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C=O)c1F
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 5-bromo-2-fluorotoluene 169 (1.0 g, 5.29 mmol.) in anhydrous THF (4 mL) cooled in dry ice/acetone bath was added a 2 M solution of lithium diisopropylamide (2.6 mL, 5.2 mmol.). The reaction mixture was stirred for 1 hour in the dry ice/acetone bath. Anhydrous dimethylformamide (0.46 g, 6.35 mmol.) was added in a dropwise manner. The reaction mixture was allowed to warm to room temperature in 3 hours. Ethyl acetate (100 mL) was added. The organic layer was washed with 1 N hydrochloric acid, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to afford 5-bromo-2-fluoro-3-methylbenzaldehyde 170 (1.08 g, 4.98 mmol.). The crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[CH2:13]([OH:15])[CH3:14]>CCOCC>[ClH:1].[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6](=[NH:7])[O:15][CH2:13][CH3:14]
Reactant: CCO
Reactant: N#CCOc1cccc(Cl)c1Cl
Solvent: CCOCC
Product: CCOC(=N)COc1cccc(Cl)c1Cl
Product: Cl

Procedure:
Obtained using the procedure described in section a of Example 6, starting with 219.8 g (1.086 moles) of (2,3-dichlorophenoxy)acetonitrile [prepared according to R. W. Fuller et al., J. Am. Chem. Soc. 1973, 16, 101] and 50.0 g (1.086 moles) of absolute ethanol in 1750 ml of ether. Reaction time: 16 hours at 0° C. Yld: 293.5 g (95%), m.p. 167°-169° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C@@H:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36].O>CN(C)C=O>[CH2:36]([N:13]([C@@H:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15](=[O:21])[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH:35]=[CH2:34]
Reactant: O=C([C@@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1ccccc1)N1CCCC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN([C@H](C(=O)N1CCCC1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
To a stirred solution of 2-nitro-N-(2-oxo-1-(S)-phenyl-2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (62.4 g, 160 mmol) in anhydrous dimethylformamide (300 cm3) was added potassium carbonate (44.3 g, 320 mmol). The mixture was stirred at ambient temperature for 10 minutes and allyl bromide (18.0 cm3, 208 mmol) was added dropwise over 10 minutes. The mixture was stirred for 16 hours at ambient temperature and poured into water (2000 cm3) to afford a white precipitate. The mixture was vacuum filtered, washed with water (3×200 cm3) and vacuum dried at 50° C. to constant weight to afford the title compound as a white solid (66.2 g, 96.2%) with a positive ion ESI (M−H)+430.2.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:8][C:6]1[N:7]=[C:2]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][C:24]=3[Cl:26])[CH2:20][CH2:21]2)[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CC[C@@H](COC)n1cc(Br)nc(Br)c1=O
Product: CC[C@@H](COC)n1cc(Br)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 152-154° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (d, J=1.9 Hz, 1 H), 7.12 (s, 1 H), 7.10 (d, J=1.8 Hz, 1H), 4.93-4.89 (m, 1 H), 4.33 (t, J=7.9 Hz, 2 H), 3.67 (dd, J=10.6, 5.7 Hz, 1 H), 3.55 (dd, J=10.6, 3.3 Hz, 1H), 3.35 (s, 3 H), 3.12 (t, J=7.9 Hz, 2 H), 1.92-1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C17H19N3O2BrCl2 (M+H)+: 446.0038; found m/z 446.0050.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([O:21]C)=[O:20])[C:7]=2[C:6]([CH3:23])=[N:5]1)([CH3:3])[CH3:2].C(N1C2C=C(C3C=C4C=CNC4=NC=3)C=C(C(OC)=O)C=2C=N1)(C)C.O[Li].O>C1COCC1.O>[CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([OH:21])=[O:20])[C:7]=2[C:6]([CH3:23])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2cccnc2)cc2c1c(C)nn2C(C)C
Agent: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1cnn2C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(C(C)C)c2cc(-c3cccnc3)cc(C(=O)O)c12
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylate, 1 (0.5 g, 1.618 mmol) in a mixture of THF and H2O (30 mL) was added LiOH.H2O (0.2 g, 4.85 mmol) and the mixture was refluxed at 80° C. for 8 h. THF was distilled off and the aqueous layer was adjusted to pH˜5 with 10% HCl at 0° C. and the precipitated solid was collected by filtration and dried to afford 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylic acid as an off-white solid (0.51 g). LCMS (ES+) m/z: 296.7.